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Title: Expression of Matrix Metalloproteinase 8 and other proteases in breast cancer
Author: Pilgrim, Simon
ISNI:       0000 0001 3490 5447
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2008
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The matrix metalloproteinases (MMPs) are a group of structurally-related zinc-dependent enzymes which are capable of degrading the extracellular matrix. The MMPs and the Tissue Inhibitors ofMetalloproteinases (the TIMPs, their endogenous inhibitors) have also been shown to be part ofcomplex signalling networks where their proteolytic activities process signalling molecules, at the cell surface and in the extracellular space. In humans there are 23 MMPs implicated in tumour growth, apoptosis, migration, invasion, angiogenesis and metastasis. MMP-8 (neutrophil collagenase or collagenase II) expression confers a survival advantage in a cohort of breast cancer patients. MMP-8 has been indicated to be a potential metastasis suppressor in breast cancer. There are two themes to the work ofthis thesis, the first being a detailed investigation of MMP-8 expression and localisation in breast cancer cell lines and tumours. The second theme is the identification ofnovel degradome genes potentially involved in breast cancer, using TaqMan® low density array analysis ofgene expression in normal and tumour tissues. MMP-8 expression was demonstrated by both conventional PCR and quantitative realtime PCR, and by Western blotting. In-situ hybridisation and immunohistochemistry were used to localise MMP-8 in breast cancer specimens. These studies suggest that altered expression and localisation ofMMP-8 occurs during mammary tumour progression and supports a role for MMP-8 in metastasis. TaqMan® Low Density Array technology was utilised to identify nineteen degradome genes that are significantly dysregulated in breast cancer, of which 11 have not been extensively studied before. Ofthese, nine genes were upregulated (carboxypeptidase A6, cystatin SN, cystatin SA, cathepsin D, cathepsin L2, dipeptidase I (renal), fibroblast activation protein alpha, HtrA serine peptidase 4, kallikrein-related peptidase 4) and two were significantly downregulated (reelin and Frasl related extracellular matrix protein 1). Data mining of published data shows that dysregulation ofthese candidate genes is a common theme in multiple cancers. Thus these studies have identified novel candidate breast cancer-associated genes that are worthy of further study.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available